Highlights from Recent Cancer Literature
Journal: Cancer Research (2018)

Cancer-associated fibroblasts (CAF) promote progression of head and neck squamous cell carcinoma (HNSCC), however, little is known about their activation and biology. New and colleagues studied CAFs from HNSCC and found they have a high basal level of autophagy compared with normal fibroblasts (NF). CAFs also secreted tumor-promoting factors. Paracrine secretion of IL6, IL8, and bFGF from HNSCC was partly responsible for promoting autophagy in CAFs, further maintained through autocrine signaling. Pharmalogic inhibition of Vps34, a key mediator of autophagy, attenuated xenograft growth and potentiated the effects of standard-of-care therapy.Expert Commentary: Primary patient-derived CAFs sustain an increased level of basal autophagy as compared with NFs from cancer-free patients. Decreasing autophagy significantly reduced CAF-induced HNSCC progression, suggesting autophagy inhibition combined with standard-of-care therapy might improve outcomes for patients with HNSCC.New J, Arnold L, Ananth M, Alvi S, Thornton M, Werner L, et al. Secretory autophagy in cancer-associated fibroblasts promotes head and neck cancer progression and offers a novel therapeutic target. Cancer Res 2017;77:6679–91.To sample the genome of metastases noninvasively, Adalsteinsson and colleagues developed a novel method, ichorCNA, that robustly identifies normal tissue content from ultralow passage whole genome sequencing. IchorCNA simultaneously predicts segments of somatic copy number aberrations (SCNA) and estimates of tumor fraction, while accounting for subclonality and tumor ploidy. Applying this method, including in silico mixing controls, they could detect the fraction of normal tissue and subsequently detect both SCNAs and somatic single nucleotide variants (SSNV). A high concordance between SCNAs and SSNVs was detected in cell-free DNA with matched biopsies. Across tumor types, they observed high concordance between somatic events detected in biopsies and cell-free DNA, useful for monitoring of metastatic disease.Expert Commentary: As serial biopsy is not practical, the authors provide a feasible method to study the evolution of metastatic cancer during therapy and to monitor response to treatment.Adalsteinsson VA, Ha G, Freeman SS, Choudhury AD, Stover DG, Parsons HA, et al. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nature Commun 2017;8:1324. DOI: 10.1038/s41467-017-00965-y.By comparing the ratio of nonsynonymous and synonymous (selectively neutral) mutations in protein encoding genes, Martincorena and colleagues examined evolutionary pressures that drive tumorigenesis. Using the The Cancer Genome Atlas database and five healthy tissues as a reference point, they identified ∼1-10 driver mutations per tumor, almost all of which resulted in positive selection. Almost 50% of the driver mutations identified occurred in previously undescribed cancer genes. Interestingly, many mutations within known cancer genes were not actual driver mutations, and the frequency of such driver mutations was distinct in specific tumor types. While driver mutations were also identified in genes that resulted in negative tumor selection, such mutations represented a minority of the total mutations. Furthermore, a large number of tumor-specific mutations were evolutionarily neutral and thus well tolerated by the tumor.Expert Commentary: This work shows that the number of somatic driver mutations in any tumor is quite small and that the majority of mutations found in tumors do not contribute to tumorigenesis.Martincorena I, Raine KM, Gerstung M, Dawson KJ, Haase K, Van Loo P, et al. Universal patterns of selection in cancer and somatic tissues. Cell 2017;171:1029–41.Lung cancers show sex-specific differences in biology and outcome due to estrogen signaling. Rao and colleagues provide evidence that receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is a downstream mediator of estrogen signaling in non-small cell lung cancer (NSCLC). They found that RANK was expressed in NSCLC, enriched in KRAS mutant NSCLC, and associated with a worse outcome. RANK was required for tumor initiation and progression in a transgenic KrasG12D mouse lung cancer model and led to increased stem-like cells through regulation of mitochondrial respiration. Finally, RANK ligand was expressed at higher levels in female NSCLC patients, and RANK decreased survival in an estrogen-dependent manner in female mice.Expert Commentary: These studies provide both a mechanism for sex-specific differences and a rationale for future studies with FDA-approved RANK inhibitors in female patients with KRAS mutant NSCLC.Rao S, Sigl V, Wimmer RA, Novatchkova M, Jais A, Wagner G, et al. RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer. Genes &amp; Dev 2017;31:2099–112.Receptor clustering and signaling is fundamentally important for all aspects of biology. Seguin and colleagues discovered that the carbohydrate-binding protein galectin-3 clusters cell surface adhesion receptors αvβ3 integrins, resulting in increased KRAS signaling. The galectin-3–induced integrin clusters enable oncogenic KRAS features like anchorage-independent growth and macropinocytosis for increased nutrient uptake. Importantly, disrupting the integrin-galectin-3 link with a clinically active polysaccharide effectively interferes with KRAS clustering and inhibits tumor growth of non-small cell lung cancer patient-derived xenografts and murine KRASV12-driven lung tumors in vivo.Expert Commentary: Antagonism of integrin-ligand interactions has not been clinically effective, possibly owing to numerous ligand-independent functions of integrins in cancer. These data demonstrating efficacy of targeting integrin clustering highlight new opportunities for therapeutic inhibition of integrin-dependent oncogenic signaling.Seguin L, Camargo MF, Wettersten HI, Kato S, Desgrosellier JS, von Schalscha T, et al. Galectin-3, a druggable vulnerability for KRAS-addicted cancers. Cancer Discov 2017;7:1464–79.Mechanistic target of rapamycin (mTOR) interacts with hedgehog signaling, however, the underlying mechanisms are not well understood. Wu and colleagues conditionally deleted Raptor and Rictor, critical components of the mTORC1 and mTORC2 complex, respectively, in cerebellar granule neuron (cGNP) precursors, cells of origin for Sonic Hedgehog (SHH) medulloblastoma. Deletion of Raptor but not Rictor impaired hedgehog signaling and reduced numbers of cGNP. Disruption of mTORC1 but not mTORC2 in a SHH medulloblastoma model (SmoM2loxp/+) blocked medulloblastoma formation. The translational activity of a downstream effector of mTOR, 4EBP1, was required for canonical hedgehog signaling downstream of Smo. The 4EBP1 protein levels were elevated in human SHH medulloblastoma, and treatment of SmoM2loxp/+ mice with an mTOR kinase inhibitor significantly prolonged survival.Expert Commentary: The mTOR kinase contributes to therapy resistance to Smo inhibition. This study characterizes cross-talk between mTORC1 and SHH signaling in both cerebellar development and medulloblastoma, and provides a potential new treatment option.Wu CC, Hou S, Orr BA, Kuo BR, Youn YH, Ong T, et al. mTORC1-mediated inhibition of 4EBP1 is essential for hedgehog signaling-driven translation and medulloblastoma. Developmental Cell; published online October 3, 2017; doi: 10.1016/j.devcel.2017.10.011.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.